Advances in surgical and radiation treatment of primary tumors have left metastasis as perhaps the most devastating aspect of cancer. In operable cases, primary tumor growth or local recurrence is rarely a cause of death. Instead, at present, roughly one-third of cancer victims with operable tumors ultimately succumb to metastatic disease.
The hematogeneous metastatic process begins with the detachment of tumor cells from the primary tumor followed by intravasation with direct shedding of tumor cells into circulation. Although most tumor cells in circulation are quickly destroyed by various mechanisms, a few viable cells may be arrested in the microvasculature or otherwise may adher to endothelial surfaces.
While in the blood stream or shortly after adhesion to endothelium, intravascular cancer cells become surrounded by thrombotic material consisting of platelets, erythrocytes and fibrin. Thrombus formation appears to be a significant event in the establishment of tumor colonies in the capillary beds of various organs. Blood platelets also appear to play an important role in tumor metastasis; it has been demonstrated that many metastasizing tumor cell lines induce platelet aggregation both in vitro and in vivo. Furthermore, upon aggregation, platelets release a substance or substances which promote tumor growth.
Since tumor cell-platelet interactions play a role in tumor metastasis, several laboratories have examined anticoagulants and anti-aggregating agents, such as heparin, warfarin (Hagmar and Norrby, Vol. 5 Int. J. Cancer, pp. 72-84, [1970]; Lione and Bosmann, Vol. 2 Cell Biol. Int. Res., pp. 81-86 [1972]; Hoover and Ketcham, Vol. 35 Cancer, pp. 5-14 [1975]); aspirin (Gasic et al., Lancet II, pp. 932-933 [1972]; Wood and Hilgard, Lancet II, pp. 1416-1416 [1972]; Hilgard et al., Vol. 86 Z. Krebsforsch., pp. 243-250 [1976]) and dipyridamole (Hilgard in Interaction of Platelets and Tumor Cells, pp. 143-158, Jameson [ed.] [1982]; Ambrus et al. in Platelets: A Multidisciplinary Approach, pp. 467-48, de Gaetano [ed.] [1982]) to reduce the incidence of tumor metastasis without treating the tumor per se in experimental animal models. However, the results of many of these studies were inconclusive. Recent reports by Honn et al., 212 Science, pp. 1270-1272 (1981) have shown that i.v. injection of prostacyclin (PGI.sub.2), a potent inhibitor of platelet aggregation, reduces pulmonary tumor colonization by tail vein injected B16 amelanotic melanoma cells in mice.
There exists a need for new and effective agents for treatment and prevention of metastasis which do not treat the primary tumor per se but which can be used in conjunction with surgery and/or tumor chemotherapy. In particular, agents that are capable of reducing the incidence of metastasis by inhibiting platelet aggregation without harmful side-effects would satisfy a long-felt medical need.